Drug Distribution Flashcards
What needs to happen to a drug once it has been absorbed?
Needs to be distributed to the tissue
What is drug distribution?
Refers to the reversible transfer of a drug between the blood and the extra-vascular fluids and tissues of the body
What is tissue distribution impacted by?
Plasma protein binding
Tissue perfusion
Membrane characteristics (blood brain barrier, blood-testis/ovary barrier)
Transport mechanisms
Diseases and other drugs
Eliminations
What do many drugs bind to?
Proteins such as albumin or alpha1-glycoprotein
When is the drug biologically active?
When it is unbound
What can drugs binding to proteins be described as?
Reversible
What is the amount of drug bound changed by?
Renal failure
Hypaalbuminaemia
Pregnancy
Other drugs
Saturability of binding
What does a small change in the amount of unbound drug lead to?
A massive change in the drug action, for example:
A drug that is 96% bound changes to 92%, so the amount of active drug has doubled
What is the therapeutic range?
Concentration of drug to achieve the desired therapeutic effect
What is the ability to achieve the therapeutic range affected by?
Volume of distribution
Clearance
Half life
What is apparent volume of distribution (Vd)?
Volume of plasma that would be necassary to account for the total amount of drug in a patient’s body, if that drug was present throughout the body at the same concentration as found in the plasma (expressed as L/kg)
What is the apparent volume of distribution (Vd) expressed as?
L/kg
What is a formula that describes the apparent volume of distribution?
Vd = (total amount of drug in the body) / (drug blood plasma concentration)
What does it mean if a drug has a high volume of distribution?
It will go to the tissue
What does it mean if a drug has a low volume of distribution?
It will stay in the plasma
If the drug spread through every membrane what would the volume of distribution be (Vd)?
42L (because there are 42L of fluid in the average body)
What would the volume of distribution be if the blood cannot penetrate cells?
12L
What would the volume of distribution be if the drug is highly protein bound?
3L
What is clearance (Cl)?
Theoretical volume from which a drug is completely removed over a period of time (measure in units of time ml/min)
What is clearance expressed as?
ml/min
What are the two kinds of clearance?
Hepatic clearance
Renal clearance
What is clearance a measure of?
Elimination
What does clearance depend on?
Concentration and urin flow rate for renal clearance
Metabolism and bilary excretion for hepatic clearance
What is half life (t1/2)?
Time taken for the drug concentration in the blood to decline to half of the current value
What does half life depend on?
Volume of distribution
Rate of clearance
How many half lifes does it generally take to clear a drug?
5
What does prolongation of half life increase?
Drug toxicity
What could prolongation of half life be due to?
Reduction in clearance
Large volume of distribution
What does knowledge of a drugs half life allow?
Us to work out how often a drug needs to be administered
How are most drugs given to achieve their therapeutic effect?
Chronically
When is the steady state of a drug normally obtained?
After 4 half lifes
What is time to the steady state independant of?
Dosage
What is proportional to a drugs dosage?
Steady state concentration
What are fluctuations in concentration proportionate to?
Dosage and half life
What is drug elimination?
Removal of active drug from the body
What does drug elimination determine?
The length of action of the drug
What are the 2 parts of drug elimination?
Drug metabolism
Drug excretion
Where does drug metabolism usually occur?
In the liver
Where does drug excretion normally occur?
Usually in the kidney, but also in bilary systems, lungs and milk
What are the 3 mechanisms that the kidneys use for excretion?
Glomerular filtration
Passive tubular reabsorption
Active tubular secretion
Why is renal damage important for causing drug toxicity?
The kidneys are important for excretion
How much fluid does glomerular filtration filter per day?
190L
What drug are filtered by glomerular filtration?
All unbound drugs as long as their size, charge or shape are not excessively large
What do factors that affect glomerular filtration reduce?
Clearance of the drug
What happens during tubular reabsorption?
1) As filtrate moves down the renal tubule any drug present is concentrated
2) Passive diffusion along the concentration gradient allows the drug to move back through the tubule into the circulation
Where does passive tubular reabsorption occur?
Distal tubule and collecting duct
What kinds of drugs are reabsorbed in passive tubular reabsorption?
Only unionised drugs such as weak acids
What can passive tubular reabsorption be affected by?
Renal failure
What happens to acidic/basic compounds?
They are actively secreted into the proximal tubule by active tubular secretion
What is active tubular secretion the most important system for?
Eliminating protein bound cationic and anionic drugs
How much bile does the liver secrete per day?
1L
What are the two ways that drugs can be secreted into the bile?
Actively or passively
What happens to many drugs from the bile?
They are reabsorbed into circulation which continues until the drug is metabolised in the liver or excreted by the kidneys
What is drugs being reabsorbed from the bile into circulation known as?
Entero-hepatic circulation
What does metabolism in the liver lead to?
Conjugation of the drug, the conjugated drug not being reabsorbed from the intestine
What doesn’t happen to the conjugated drug proced during metabolism in the liver?
It is not reabsorbed from the intestine
What does damage to the liver reduce?
The rates of conjugation and bilary secretion and so allows the build up or reabsorption of the drug resulting in toxicity
